PROJECT SUMMARY/ABSTRACT More than 50% of all spinal cord injuries occur at the cervical level. At this level are the phrenic motor neurons which innervate the diaphragm. Therefore, injuries at this level can lead to the inability to breathe. The overall objective of this grant proposal is to examine the changes which take place chronically in the phrenic circuitry of the cord in response to cervical spinal cord injury and investigate and optimize potential therapies that can restore breathing long after injury. Through these studies, an effective intervention can be translated to a significant population of the spinal cord injured community. In this proposal we will utilize chronic cervical spinal cord-hemisected animals which have half of the diaphragm paralyzed. In our earlier studies we observed that enzymatic (chondroitinase ABC) removal of extracellular matrix molecules, called chondroitin sulfate proteoglycans, which block plasticity, regeneration, and sprouting, led to restoration of function of the once paralyzed hemidiaphragm when administered at or near the time of injury. Recovered diaphragmatic activity was rhythmic and synchronized. In stark contrast, when the spinal cord of chronically injured animals was stimulated with chondroitinase ABC and intermittent hypoxia training, chaotic and unstructured activity resulted, suggesting slowly developing and potentially maladaptive responses to injury. However, the use of chondroitinase alone at chronic stages can promote normal rhythm and dramatically enhance properly patterned functional recovery. This grant proposal seeks to: 1) understand the time course and carefully describe the maladaptive processes that take place; 2) understand the mechanisms underlying the production of this newly discovered atypical activity at chronic time points; and 3) learn how to overcome these negative responses to injury so that interventions and rehabilitative strategies can become more effective, thereby leading to improved functional outcomes. Overall, these studies will provide insight on the basic mechanisms that underlie maladaptive, as well as functionally beneficial plasticity that can lead to robust functional respiratory motor recovery at chronic stages of spinal cord injury.